Novel 3-etherified-1,3,5(10)-triene-steroids and process thereof

ABSTRACT

Disclosed are new and novel 3-cyclobutyloxy, 3cyclopropylmethoxy and 3-cyclobutylmethoxy-1,3,5(10)-triensteroids and a method for the production thereof by reacting the corresponding 3-hydroxy steroids with a (lower)alkoxide in a (lower)alkanol followed by an appropriate tosylate or halade of cyclopropylmethyl, cyclobutyl and cyclobutylmethyl. The new and novel compounds are useful for depressing lipid levels in animals.

United States Patent Shah et al. 1

[1 1 3,689,512 Sept. 5, 1972 54 NOVEL 3-ETHERIFIED-1,3,5(l0)-TRIENE-STEROIDS AND PROCESS THEREOF [72] Inventors: Harshavadan C. Shah,Collingdale; George C. Buzby, Jl'., Philadelphia; Herchel Smith, BrynMawr, all of [73] Assignee: American Home Products Corporation, NewYork, N.Y.

22 Filed: Oct. 6, 1970 [21 Appl. Noi: 78,583

[52] US. Cl.....260/397.4, 260/239.55 C, 260/3975, 424/242 [51] Int. Cl..C07c 169/20 [58] Field of Search ..260/397.4, 397.5

[56] References Cited FOREIGN PATENTS OR APPLICATIONS 1 010 2 mit s;eep---;- @z 1 1,029,325 5/1966 Great Britain .260/39-7.5 1,055,3531/1967 Great Britain ..260/397.5 980,594 1/1965 Great Britain..260/397.4

Primary Examiner-Elbert L. Roberts Attomey-Andrew Kaiko, Joseph MartinWeigman, Dwight J. Potter, Vito Victor Bellino, Robert Wiser and DavidE. Frankhouser ABSTRACT Disclosed are new and novel 3-cyclobutyloxy, 3-

cyclopropylmethoxy and 3-cyclobutylmethoxycyclopropylmethyl, cyclobutyland cyclobutylmethyl. The new and novel compounds are useful fordepressing lipid levels in animals.

18 Claims, No Drawings NOVEL B-ETHERIFIED-l ,3 ,5(1 )-TRIENE- STEROIDSAND PROCESS THEREOF This invention is concerned with new and novelsteroid compounds useful in therapy and as intermediates for theproduction of therapeutically useful compounds wherein R is(lower)alkyl; R is selected from the group consisting of cyclobutyl,cyclobutylmethylene and cyclopropylmethylene; R is selected from thegroup consisting of hydroxy and hydrogen; R is selected from the groupconsisting of hydrogen, (lower)alkyl, (lower)alkenyl, (lower)alkynyl andha1o(lower)-alkynyl and R is hydroxy; R and R together are oxo or areconcatenated to form ethylenedioxy; the dotted lines represent optionalunsaturation; and the symbolt i indicates aor B- configuration. Ofparticular interest are the compounds of Formula (I) identified asfollows: d-3-(cyclobutyloxy)estra-1 ,3,5( l0)-trienl 7-one;

d-3-(cyclobutyloxy)-l9-nor-1 7a-pregna-l ,3,5( 10)- trien--yn- 1 7-01,methanolate;

d-3-(cyclobutylmethyloxy )estra-l ,3 ,5 l0)-tn'enl 7- one;

d-3-(cyclobutylmethloxy)-19-nor-17a-pregna-1,3 ,5( l 0 )trien-ZOV-yn- 17-01;

dll 3-ethyl-3-( cyclobutylmethoxy )gona-l ,3 ,5( l0)- trien-l7-one;

dll 3-ethyl-3-(cyclobutylmethoxy l 8,1 9-dinorl7a-pregna-1,3,5(l0)-trien-20-yn- 1 7-01;

d-3(cyclopropylmethoxy)estra-l ,3 ,5 l0)-trienl 7- one;

d-3-(cyclopropylmethoxy)-1 9-nor- 1 7a-pregna- 1,3,5( 10)-trien-20-yn-l7-01;

dl-l3-ethyl-3-(cyclobutylmethoxy )gona-1,3,5( l0)- trien- 1 73-01;

d-3 cyclobutylmethoxy)estra- 1 ,3 ,5( lO)-trien- 1 7B- 01.

Also, this invention is concerned with a process for the preparation ofa 3-substituted-l3-(lower)alkylgona-(and8-isogona)-1,3,5(10)-trien-l7-one of the formula:

III) 7 p O selected from the group consisting of cyclobutyl,cyclobutylmethylene and cyclopropylmethylene; R is selected from thegroup consisting of hydroxy and hydrogen; the dotted lines representoptional unsaturation; and the symbol 2 )indicates aor B- configurationwhich comprises forming a 3-ether derivative of a corresponding3-hydroxyl steroid compound of the formula:

wherein R and R are as hereinabove defined by the steps of:

a. reacting said 3-hydroxyl steroid with at least about one equivalentof an alkali metal or alkaline earth metal (lower)-alkoxide in a(lower)alkanol medium until conversion of the 3-hydroxyl group to thecorresponding anionic form is substantially complete;

b. displacing said (lower)alkanol medium with an inert organic solventmedium;

c. reacting the mixture of Step (b) with at least about one equivalentof a compound of the formula X-Y, wherein X is selected from the groupconsisting of cyclobutyl, cyclobutylmethyl and cyclopropylmethyl and Yis a halide or tosylate group; and

d. recovering the product of Step (c).

Special mention is made of a number of important embodiments of theabove-described process invention. These are, respectively:

A process as next defined above wherein, in Step (a), said alkali metal(lower)alkoxide is sodium methoxide and said (lower)alkanol medium ismethanol.

A process as first defined above, wherein, in Step (b), said inertorganic solvent medium is dimethylsulfoxide.

A process as first defined above wherein Step (c) is carried out at atemperature of from about 20 to about C. for a period of from about 2hours to about 48 hours.

A process as first defined above, wherein, in Step (c), said halide isbromide. I

A process as first defined above whereind-3-(cyclobutyloxy)estra)-l,3,5( l0)-trien-l7-one is prepared by thesteps of:

a. reacting d-estrone with sodium methoxide in methanol;

b. removing the methanol by vacuum distillation and addingdimethylsulfoxide;

c. reacting the mixture of Step (b)'with cyclobutylbromide; and

d. recovering the product by removing the solvent by distillation in avacuum.

A process as first defined above wherein d-3- (cyclobutylmethyleneoxy)estra-l ,3 ,5( l0)-trien-l 7-one is prepared by the steps of: t

a. reacting d-estrone with sodium methoxide in methanol;

b. removing the methanol by vacuum distillation and addingdimethylsulfoxide;

c. reacting the mixture of Step (b) with cyclobutylmethyl tosylate; and

d. recovering the product by extracting the mixture of Step with etherand water and distillation in a vacuum.

A process as first defined above wherein dl-13-ethy1-3-(cyclobutylmethyloxy)gona-1 ,3 ,5 10 )-trienl 7-one is prepared by thesteps of:

a. reacting dl-13-ethyl-3-(hydroxy)-gona-1,3,5

( l0)17-one with sodium methoxide in methanol;

b. removing the methanol by vacuum distillation and addingdimethyl-sulfoxide;

c. reacting the mixture of Step (b) with cyclobutylmethyl tosylate; and

d. recovering the product by adding water to the mixture of Step (c),extracting with ether and distilling the extract in a vacuum.

A process as first defined above wherein d-3-(cyc1opropylmethoxy)estral,3 ,5( 10)-trien- 1 7-one 18 prepared by the steps of:

a. reacting d-estrone with sodium methoxide in methanol; b. removing themethanol by vacuum distillation and adding dimethylsulfoxide;

c. reacting and mixture of Step (b) with cyclopropylmethyl tosylate; and

d. recovering the product by adding water to the mixture of Step (0),extracting with ether and distilling the extract in a vacuum.

When used herein and in the appended claims, the term (lower)alkoxy or(lower)alkoxide contemplates hydrocarbonoxy radicals, straight andbranched chain, containing from about one to about six carbon atoms, andincludes methoxy, ethoxy, n-propoxy, ipropoxy, n-butoxy, t-butoxy,n-pentoxy, n-hexoxy, 2- methyl-pentoxy, and the like, The term(lower)alkyl contemplates hydrocarbon radicals, straight and branchedchain, containing from about one to about six carbon atoms, and includesmethyl, ethyl, n-propyl, ipropyl, n-butyl, t-butyl, n-pentyl, n-hexyl,Z-methylpentyl, and the like. The term (lower)alkenyl contemplatesmonoand di-olefinic hydrocarbon radicals, straight and branched chain,containing from about two to about six carbon atoms, and includes vinyl,alkyl, 2-methyl-2-butenyl, isopropenyl, 1,3-butadienyl,

2-pentenyl, 3-hexeny1 and the like. The term (lower)alkynyl contemplatesmonoand diacetylenic hydrocarbon radicals, straight and branched chain,containing from about two to about six carbon atoms, and includesethynyl, propargyl, 2-butynyl, 1,3,-butadynyl, 2-pentynyl 3-hexynyl andthe like. The term halo when used by itself or in association with(lower)alkyl, (lower)alkenyl or aryl contemplates halogens, and includesfluorine, chlorine, bromine and iodine. The phase inert organic solventcontemplates solvents which are organic and are not susceptible toreaction with the steroids, halides and tosylates contemplated hereinunder the conditions exemplified and includes, for example, chloroform,tetrahydrofuran (THF), benzene, dioxane, dirnethylformamide (DMF),dimethylsulfoxide (DMSO), 1,2-dimethoxyethane and the like. Alltemperatures used herein and in the appended clairns are in degreesCelsius unless otherwise indicated.

Starting materials of Formula (111) are commercially available or canreadily be prepared by techniques familiar to those skilled in the art.For example, d-estrone, a compound of Formula (111), wherein R ismethyl, C8(H) is [3 and R is hydrogen, is an item of commerce. The3-hydroxy13-(lower)alkylgona-l,3,5 (lO)-triene-l7-ones of Formula (III)are prepared by means exemplified in U.S. Pat. No. 3,488,258 and U.S.Pat. No. 3,502,698. The 3-hydroxy-13-(lower)alkyl-8-isogona-l,3,5(10-triene-17-ones of Formula (III) are prepared by meansexemplified in U.S. Pat. No. 3,407,217. The'3-hydroxy-13-(lower)alkyl-1,3,5 (10),7-tetraene-17-ones of Formula(III) are prepared by means exemplified by R. P. Stein, G. C. Buzby, Jr.and l-L'Smith in copending U. S. Pat. application, Ser. No. 760,212,filed Sept. 16, 1968, now U.S. Pat. 3,555,015. The 3 hydroxy-l3-(lower)alkylgonal,3,S(10),8(9)-tetraene-17-ones of Formula (III) areprepared by means exemplified in U.S. Pat. No. 3,391,169. The3-hydroxy-13-(lower)alkylgona-1,3,5 (10),9(11)-tetraene-l7-ones ofFormula (III) are prepared by means exemplified in U.S. Pat. No.3,391,170. The 3-hydroxy-l3-(1ower)alkylgona-1,3,5 (l0)-triene-l7-ones(and the 16-hydroxy analogs thereof) of Formula (111) are prepared bymeans exemplified by G. A. Hughes and H. Smith in copending U.S. Pat.application Ser. No. 534,353, filed Mar. 15, 1966 now U.S. Pat. No.3,519,714 The 3-hydroxy-l3- (lower)alkylgona-1,3,5(10),6,8,(9)-pentaene-17-ones of Formula (III) are prepared by meansexemplified in U.S. Pat. No. 3,475,468.

The 3-hydroxy-13-(lower)alkylgona-1,3,5(10),6- tetraene-l7-ones areprepared from the 3-methoxyl 3- (lower)alkylgona-l,3,5(10)-trienes ofU.S. Pat. Ser. No. 534,353, filed Mar. 15, 1966 by introducing a 6- ketogroup with t-butyl chromate in carbon tetrachloride; reduction to the6-01 with a hydride, such as sodium borohydride; and dehydrating, aswith POCl in dimethylformamide, or p-toluenesulfonic acid (or iodine) inrefluxing benzene to introduce the double bond between C and C accordingto procedures such as those described in G. C. Buzby, Jr.; G. H.Douglas, C R. Walk and H. Smith, Excerpta Medica Int. Cong. Series No.132 Proceedings of the Second Int. Congress on Hormonal Steroids, Milan,May 1966, p. 311; then cleaving the 3methoxy group in a known way, e.g.,by refluxing with pyridine hydrochloride or by cleavage with a Grignardreagent according to U.S. Pat. No. 3,436,411. Introduction of the 1601-or B-hydroxy group is also accomplished in known ways. For example, thesubstrates are oximated in the presence of an alkyl nitrite and the16-oximino compound is hydrolyzed, for instance, by reduction with zincand a lower alkanoic acid to give a 16-ketone. This is reduced to the1601-01, for instance, with an alkali metal and lower alkanol or bycatalytic hydrogenation to give the 16Bol. These methods are exemplifiedin U.K. Pat. No. 115,954.

The cyclopropylmethyl, cyclobutyl and cyc1obuty1- methyl halides andtosylates are items of commerce or may be prepared by means well knownto those skilled in the art. For example, cyclobutylbromide is availablecommercially from Ash Stevens, lnc., Detroit, Michigan 48202 or may beprepared by the method described in Cason et al., J. Org. Chem., 14,31-36, 1949. Cyclobutylmethyl tosylate is prepared fromcyclobutanecarboxylic acid, available commercially from Ash Stevens,Inc., by reducing to cyclobutanmethanol using the procedure described inKuivila et al, JACS, 74, 4953-54, 1952, and Organic Reactions, VolumeVI, John Wiley, followed by conversion to the tosylate using the methodof Braker et al, JACS, 69, 866-69, 1947. Similarly, cyclopropylmethanol,available commercially from Aldrich Chemical Company Inc., is convertedto cyclopropylmethyl tosylate using the method of Braker et al., supra.

In carrying out Step (2.) of the instant process, the steroid of Formula(III) may be added to the mixture of the alkali metal (lower)alkoxideand the (lower)alkanol at any convenient temperature, e.g. from about toabout 50 C., or even higher. It is preferred to use at least about oneequivalent amount of the alkali metal (lower)alkoxide, or a slightexcess, e.g. up to about a 10 percent excess, based on the steroidstarting material. The reaction forming the anion salt, especially atabout 25 C., is quite rapid and is substantially complete almostinstantaneously.

In carrying out step (b), displacement of the (lower)- alkanol by theinert organic solvent, resort can be made to adding the solvent andfractionally distilling off the (lower)-alkanol. However, especially incases where the respective boiling points are close, it is preferred andconvenient first to distill off the (lower)alkanol, then to resuspendthe residue in the desired volume of inert organic solvent.

In carrying out Step (0), reaction of the product of Step (b) with theether forming agent can be added to the mixture at temperatures of fromabout 10 to about 150 C., but preferably at from about to about a 100 C.It is preferred to use at least about one equivalent amount of the etherforming agent, or a slight excess, e.g., up to about a 10 percentexcess, based on the steroid. The reaction forming the desired etherproduct is substantially complete, depending on the temperature, in fromabout 2 to 48 hours.

After reaction is complete, recovery of the product of Formula IIaccording to Step (d) is accomplished by conventional methods. Forexample, sometimes the product can be induced to precipitate by coolingthe mixture, especially if it first has been concentrated, then theprecipitate is recovered by filtration. One especially useful means isto distill off all of the reaction solvent, leaving the product as aresidue. To proceed in this manner, the solvent is distilled off in avacuum. The mixture then can be extracted with a water immiscibleorganic solvent, such as ether and dried. Evaporation of the solventleaves the product of Formula II as a residue. If desired, it may befurther purified by chromatography: it is dissolved in benzene andpassed through a column of active silica gel, Florex. The eluates can becombined and evaporated. The residue can often be induced to crystallizeby trituration with ether or isopropanol and can be recrystallized froma (lower)alkanol.

The time and temperature ranges used in describing the aforementionedprocess steps simply represent the most convenient ranges consistentwith carrying out the reaction in a minimum of time without unduedifficulty. Thus, reaction temperatures appreciably below these can beused, but their use considerably extends the reaction time. Similarly,reaction temperatures appreciably below these can be used, but their useconsiderably extends the reaction time. Similarly, reaction temperatureshigher than those mentioned can be employed with a concomitant decreasein reaction time, although purity of the product may be somewhatdecreased.

The sources for the starting materials of Formula III have beenspecified hereinabove. Generally, all can be prepared by totallysynthetic processes described by Douglas, Graves, Hartley, Hughes,McLoughlin, Siddall and Smith in J. Chem. Soc., 1963, pages 5077-94.

In the product of a total synthesis which has not included a suitableresolution stage the compounds prepared by the invention will be presentas racemates. Using a convention approved by Fieser and Fieser,Steroids, p. 336 (1959), the compounds designated as the d-forms are theenantiomers corresponding in configuration at C-l3 to that of thenatural hormone estrone. The corresponding enantiomorphs areconsequently designated the l-forms and the racemates the d-forms.Racemates will be depicted by structural formulas which show only theenantiomorphs of the dconfiguration.

The 3-ether steroids of Formula (II) are further reacted to provideother pharmacologically active compounds of Formula (I). For example:the l7-keto group of the compounds of Formula (H) can be ethynylated,such as with acetylene and lithium acetylide or lithium chloroacetylide,to provide the corresponding lz-ethynyl or chlorethynyl-l7B-ol steroids;the 17- keto group of the compounds of Formula (II) can be reduced to a17,8-hydroxy group by treatment with a reducing agent, such as sodiumborohydride; the 17- keto group of the compounds of Formula (II) can beconverted to the corresponding l7a-alkyl, l7a-alkenyl orl7a-alkenyl-l7B-ol by treatment with the appropriate magnesium bromidederivative, such as methyl magnesium bromide; the l7-keto group can beconverted to a 17,17-ethylenedioxy group by treatment of ethylene glycolcatalyzed with p-toluenesulfonic acid.

The compounds of this invention possess extremely enhanced anti-lipemicactivity in animals when tested asfollows:

Male weanling rats are fed a hypercholesterolemic diet for three weeks.Serum cholesterol is determined on 0.01 ml. of serum separated from tailblood collected in a capillary tube. Groups of rats with equal averageserum cholesterol are given the test compound orally once a day bysyringe for three days. Serum cholesterol is determined in the morningof the fourth day. Anti-lipemic activity is demonstrated by a loweringof the serum cholesterol. Potency is expressed as the percent activityof a concomitantly run standard compound,dl-l3-ethyl-3-methoxy-8a-gona-1,3,5(10)- trien-l 73-01.

Certain compounds of Formula (I) require special notice when tested inthe above-described procedure. These compounds followed by the presentactivity when compared to the test standard compound are:

d-3-(cyclobutyloxy)estra-1,3 ,5( l 0 )-trienel 7-one (600 percent);

d-3-(cyclobutyloxy)- l 9-norl 7a-pregna-l ,3,5( 10 triene-20-yn-l7-ol,methanolate (greater than percent);

d-3-(cyclobutylmethyloxy 1 9-nor- 1 7a-pregna- 1,3,5(l)-trien-20-yn-l7-ol 1,800 percent); and

d-3-(cyclobutylmethoxy)estra-1 ,3 ,5 10)-trien- 1 7B- ol (175 percent).

The compounds of Formula (1) demonstrated nonfeminizing active lipiddepression in animals when tested as follows: 7

Adult male rats receive test compound daily for nine days. At autopsy onthe tenth day body and testis weights are taken and a blood sample issubmitted to biochemistry for cholesterol analysis. Compounds producingdepression in blood lipid at doses that are not feminizing are ofparticular interest. The standard is estrone.

Compounds of Formula (I) of particular interest and usefulness resultingfrom the above-described test procedure include:

d-3-(cyclobutyloxy)estra-1 ,3 ,5( l0 )-trien-1 7-one;

d-3-(cyclobutylrnethoxy)estra-1 ,3 ,5 10)-trien- 1 7- one;

d-3-(cyclopropylmethoxy)-19-norl 7a-pregna- 1,3,5( l0)-trien-20-yn-17-ol; and

dll 3-ethyl-3-(cyclobutylmethoxy )gona-l ,3,5( 10)- trien- 1 73-01.

As is mentioned hereinabove, the compounds prepared by this process havehigh anti-lipemic activity. This makes them useful to treat conditionsin mammals responsive to treatment to lower blood lipid level of mammalsand can be used whenever anti-lipemic agents are indicated, such as inthe treatment of various hyperlipidaernias or where the incidence ofatherosclerosis is to be minimized. The products prepared by the instantprocess are also useful as intermediates for the preparation of othersteroids, which have hormonal or other useful activities. The compoundsof the present invention, Formula (I), are effective antilipemic agentswhen administered to animals in a dosage range of from about 0.05 mg. upto about 200 mg. of active compound administered daily. Particularlyinteresting activity is demonstrated in the range of 0.1 mg. up to about10.0 mg. administered daily. The administration may be at one time or inspaced, divided portions.

The products of Formula I prepared by this invention can be used inassociation with a pharmaceutically acceptable carrier. They can beformulated in liquid or solid forms, for instance as capsules, tablets,suppositories, powders, dispersible granules, cachets, and the like bycombining them with conventional carriers. Such conventional carriersinclude magnesium carbonate, or stearate, talc, sugar, lactose, pectin,dextrin, starch, gelatin, tragacanth, methyl cellulose, sodiumcarboxymethyl cellulose, low melting wax or cocoa butter. Diluents,flavoring agents, solubilizers, lubricants, suspending agents, bindersor tablet-disintegrating agents can be used. Powders or tabletspreferably contain or to 99 percent of the active constituent. Theactive steroid can be formulated with an encapsulating material with orwithout other carriers.

Liquid preparations such as solutions, suspensions or emulsions can alsobe used. Such preparations include dispersions in a pharmaceuticallyacceptable carrier such as arachis oil or sterile water, preferablycontaining a nonionic surface active agent such as fatty acid esters ofpolyhydroxy compounds, e.g., sorbitan, aqueous starch in sodiumcarboxymethylcellulose solutions, aqueous propylene glycol orpolyethylene glycol. Thus, a water-propylene glycol solution can be usedfor parenteral injection and aqueous suspensions suitable for oral usecan be made by utilizing natural or synthetic gums, resins, methylcellulose or other wellknown suspending agents.

The composition can be in unit dose form in which the dose unit is forinstance from about 0.1 to about 200 mg. of each active steroid. Theunit dose form can be a packaged composition, e.g., packeted powder,vials or ampules or, for example, in the form of capsules, cachets ortablets or any number of these in packaged form. The pharmaceuticalcompositions can also consist substantially solely of the. activesteroid when this is in unit dose form. When used for the purposesstated above, the dosage of the compounds will vary with the conditionbeing treated, but a good starting dosage in general will be in therange established for estradiol (Merck Index, Seventh Edition, p. 416[1960]).

Merely by way of illustration, in a standard antilipernic assay in maleweanling rats of about 100 g. means body weight fed on ahypercholesterolemic diet for three weeks,d-3-(cyclo-butylmethyloxy)-19nor-l 7 a-pregna-l ,3,5( 10 )-trien-20-yn-1 7-ol demonstrated significant extreme lowering of the serumcholesterol level following administration of 0. 1 mg. perorally dailyfor three days.

Of course, as will be clear to those skilled in the art, in addition tosubstrates designated by the formula above, the process broadly can beapplied to obvious chemical equivalents thereof but differing therefromin the sense of having other functional groups attached to the steroidnucleus, whenever such groups do not themselves interfere or becomeafiected by the process, unless, in exceptional instances, this is adesired effect. Similarly, the steroid nucleus may contain anysubstitution at positions other than at 16 or 17, as, for example,6-methyl. Broadly stated, therefore, useful substrates would berepresented by the formula wherein Z is acyclopentanopolyhydrophenanthrene nucleus, with an aromatic A-ringmonosubstituted by -OH which, on the formation of an ether derivative ofthe form ZOR wherein R is as set forth in Formula (I), would provide aproduct with high anti-lipemic activity.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The following examples aregiven by way of illustration and are not to be construed as limitationsof this invention, variations of which are possible without departingfrom the scope and spirit thereof.

EXAMPLE I d-3-(Cyclobutyloxy)estra-l ,3 ,5( 10 )-trien 1 7-one Add withstirring to a solution of sodium methoxide (0.6 g.) in methanol (100ml.), d-estrone (3.0 g.). Stir additional one-half hour. Remove themethanol in vacuo. Transfer the dry salt to a 3-necked flask anddissolve it in dimethyl-sulfoxide (DMSO) ml.). Add

three ml. of cyclobutylbromide and heat the mixture with stirring at6070 C. (water bath) for 3 hours. Add 3 ml. of cyclobutylbromide andheat with stirring for four more hours. Let stand at room temperatureovernight.

Add water (300 ml.) with stirring. Extract the mixture with ether.Remove the solvent from the dry extract in vacuo. Dissolve the residuein benzene (50 ml.) and filter off the insoluble (starting material).Filter the benzene solution through a column of Florex. Remove thesolvent from the filtrate in vacuo. Recrystallize the residue, a whiteclear oil, from methanol to give 1.39 g. of a product, m.p. 130136 C.

Prepare an analytical sample by one more recrystallization (1.39 g.)from methanol to give the title product (1.01 g.), m.p. 135137 C. A55,5.72, 8.19 u. [a],; =+l34 (c=1, CHCI ANALYSIS Calcd. for C I-1 C, 81.44;H, 8.70.

Found: C, 81.08; H, 8.47.

EXAMPLE II d-3-(cyclobutyl methyloxy)estra-l ,3,5( l0)-trien-1 7- oneAdd with stirring, to a solution of sodium methoxide (0.6 g.) inmethanol (100 ml.), d-estrone (3.0 g.). Stir an additional one-halfhour. Remove methanol in vacuo. Dissolve the dry salt in DMSO (75 ml.),add cyclobutylmethyl tosylate (2.0 g.) and stir the mixture at roomtemperature for 6 hours and let stand at room temperature overnight. Addwater (300 ml.) with stirring. Extract the mixture with ether, removethe solvent from the dry extract in vacuo and dissolve the residue inbenzene (50 ml.). Filter, pass the filtrate through a column of Florex.Remove the solvent in vacuo. Recrystallize the residue from methanol togive the title product (1.15 g.), m.p. ll4ll8 C. 5.83 p; [01],, +1 32(0+1, CHCl ANALYSIS Calcd. for C I-1 0 C, 81.61; H,

Found: C,8l.80; H, 8.95.

EXAMPLE lII d-3-(Cyclopropylmethoxy )estra- 1 ,3 ,5( l0 )-trien-l 7- oneAdd, with stirring, to a solution of sodium methoxide (0.6 g.) inmethanol (100 ml.), d-estrone (3.0 g.). Stir an additional one-halfhour. Remove methanol in vacuo. Dissolve the dry salt in DMSO (75 ml.)and add, with stirring, cyclopropylmethyl tosylate (2.0 g.). Stir themixture at room temperature for six hours and let stand at roomtemperature overnight. Add water (300 ml.) with stirring. Extract themixture with ether. Remove the solvent in vacuo from the dry extract.Dissolve the residue in benzene. Filter. Pass the filtrate through acolumn of Florex. Remove the solvent from the filtrate in vacuo.Recrystallize the residue from methanol to get the title product (650mg.), mp. l25-127 C. 511. 5.72 p. [a],, =+l42 (e -=1, CHCl EXAMPLE IVThe procedures set forth in Examples 1, I1 and Ill are repeated,substituting for d-estrone, stoichiometrically equivalent amounts of thefollowing steroidal phenols:

and the following 3-etherified-steroids are respectively obtained:

1. EXAMPLE v d-3-(Cyclobutyloxy)-19-nor-l7a-pregna-l,3 ,5 l

trien-20-yn- 1 7-ol, methanolate Suspend d-3-(cyclobutyloxy)estra-1,3,5(l0)-trienl7-one (1.18 g.) in dry dimethylsulfoxide -30 ml.) in a3-necked flask, equipped with a drying tube, magnetic stirrer and a gasinlet. Saturate the suspension with dry acetylene gas for one hour. Addlithium acetylide-ethylenediamine complex in two aliquots of 1.0 g.),one and one-half hour apart, continuing passing of acetylene andstirring, for a total of three hours after the first addition of lithiumacetylide. Pour the brown mixture into ice water and let stand forone-half hour. Extract the mixture with ether, remove the solvent fromthe dry extract invacuo. Dissolve the residue in benzene and filterthrough a column of Florex. Remove the solvent from the benzene solutionin vacuo. Recrystallize the residue from methanol to give the titleproduct (770 mg.), mp. l20-122 C (Solvate) E3; 3.12, 8.17 t; [a],, =+5(0 1, CHCl ANALYSIS Calcd. for C H O -CH OH: C, 78.5 H, 8.98.

Found: C, 78.32; H, 8.84.

EXAMPLE VI d-3-(Cyclobutylmethyloxy 1 9-nor- 1 7a-pregnal,3,5()-trien-20-yn 1 7-01 Suspend d-3-(cyclobuty1methyloxy)estra-1 ,3,5( 10)-trien-l7-one (1.83 g.) in dry DMSO (about 50 ml.) in a dry 3-neckedflask equipped with a drying tube, magnetic stirrer and a gas inlet.Saturate the suspension for one hour with dry acetylene gas. Add lithiumacetylideethylenediamine complex (2.0 g.) and stir with passingacetylene gas for three hours. Pour the mixture into ice water and letstand for one-half hour. Extract the mixture with ether. Remove thesolvent from the dry extract, dissolve the residue in benzene (aboutSOml.) and filter through a column of Florex. Remove the solvent from thefiltrate in vacuo. Dissolve the residue in dichloromethane, add charcoaland heat on a steambath. Filter through a-bed of Super Cel. Remove thesolvent from the filtrate in vacuo. Recrystallize the residue from asmall volume of hexane to get the product (725 mg.),.m.p. 80-85 C.; 33;,2.95, 3.1 t. [011 =4 (c=1, CHCl ANALYSIS Calcd. for C H O 8.85.

Found: C, 81.61;H, 8.518138 8.50.

EXAMPLE VII d-3-(Cyclopropylmethoxy 19-nor- 1 7a-pregna- 1,3 ,5(10)-trien-20-yn-17-ol Suspend d-3-(cyclopropylmethoxy)estral ,3,5( 10)-trien-17-one (560 mg.) in dry DMSO ml.) in a 3- and one-half hour apart,continuing passing of acetylene gas and stirring for a period of threehours after the first addition. Pour the brown mixture into ice-waterand let stand for one-half hour. Extract this mixture with ether. Removethe solvent from the dry extract in vacua. Dissolve the residue inbenzene and filter through a column of Florex. Remove the solvent fromthe filtrate in vacuo. Dissolve the oil in ether and filter throughcotton. Remove the ether on asteambath. Pump the residue into a dryglass (400 mg.) )3. 2.95, 3.09 p. ANALYSIS Calcd. for C l-1 0 C, 82.24;H, 8.63.

Found: Q8196; H.880.

EXAMPLE vm The procedures set forth in Examples V, VI and VII arerepeated, substituting for d-estrone, stoichiometricallyequivalentamounts of the etherified l7-one steroids provided in Example IV and thefollowing 17-aethynyl-17-B-ol steroids are obtained:

EXAMPLE 1x d-3-(Cyclobutylmethoxy )estra-l ,3 ,5( l)- trienl 7B-olDissolve d'-3-(cyclobutylmethoxy)estra-l ,3,5( trien-l 7-one (1.0 g. inmethanol (75 ml.). Add sodium borohydride 1.0 g.) with stirring in smallaliquots, over a period of 1 hour. Stir the mixture for three hours. Addwater (75 ml.) slowly with stirring. Extract the mixture with ether.Remove the solvent in vacuo from the dry ether extract. Dissolve theresidue in dichloromethane, add charcoal and heat on a steambath. Filterthrough a bed of Super Cel. Remove the solvent from the filtrate invacuo. Recrystallize the residue from methanol to get (460 mg.) thetitle product, mp. ll23 C. A52: 2.93 .4.. [01],, =+67 (c=l CHCl wANALYSIS Calcd. for C H O -l41 CH OH: 80.12; H, 9.54.

Found: C, 80.41;H, 9.88.

EXAMPLE X The procedure of Example IX is repeated, substituting ford-3-(cyclobutylmethoxy)estra-l,3,5(l0)-trienl7-one, stoichio-metricallyequivalent amounts of the 3-etherified-l7-one steroids provided inExamples I, III and IV and the following 3-etherified-l7Bol steroids areprovided:

cu, C-IKB) A'"" a-OH H CH,CH, A H D-Cfli- CH, C-HUB) A H H[ CH2-EXAMPLEXI d-3-Cyclobutyloxyl 7, l 7-( ethylenedioxy)estral,3,5(10)-triene Reflux d-3-( cyclobutyloxy )estra-l ,3 ,5( l0 )-trienl 7- one(2.5 g.) in benzene ml.) and ethylene glycol (22 ml.)withp-toluenesulfonic acid (0.3 g.)'for sixteen hours. Cool thesolution, pour into saturated sodium bicarbonate and extract with ether.Wash the organic layer with brine, dry and evaporate. Crystallize theresidue from ethanol (40 ml.) to obtain the title product.

In a similar manner, using the appropriate starting materials ofExamples II, III and IV, the following 17, l 7-ethylenedioxy-steroidsare provided:

R 08 A R,

cu, C-H(a) H -oHi- -Hux) H Voma h uB) a-OH CHz- (CI-1,),CHCH, C-H( [3) HCH,

CH,(CH,),CH, c-mp p-on -om- 15 l6 CHaCH' N H D cH,cH, A1 H 335911. l

cH c-mp) M a-OH .5 H, c-mm 'a-OH c c :)s i

cH, -A 'H cH, A H CH,CH,-

cH,cH A ,H DABHP CH3CH, A vH cH,(cH, -i -CH2 cH, C-H(B) AW" H V cH,c-Hqav- H cH, ,cH- -om- EXAMPLE XII EXAMPLE XIII d-3-Cycl0 u yl0xy l7a-m y d-2 l -Chloro-3-( cyclobutyloxy I 9-norl 7a-pregna- Dissolved-3-(cyclobutyloxy)estra-1,3,5( l0)-trienl7-one (4 g.) in benzene (200ml.). Add dropwise, with stirring every five minutes, an etherealsolution of methyl magnesium bromide (23.2 ml.; from the metal, 1.6 g.).Reflux the resulting solution for one hour, cool, pour onto ice, acidifywith 5N hydrochloric acid, and extract with ether. Wash the organiclayer with saturated aqueous sodium bicarbonate, then water. Dry,evaporate the solution, and recrystallize the residue from isopropanolto obtain the title compound.

In a similar manner, using the appropriate starting materials ofExamples II, III and IV, the following com- 7 nus CH,CH, A! H QH,

A on O (in, (am 4; A'" H cmcu, A H v -cH,

cu, AW) H l -om- EXAMPLE XIV dl-l 3-Ethyl-3-(cyclobutylmethyloxy)gonal,3,5()-trien-17-one Add, with stirring, to asolution of sodium methoxide (0.7 g.) in methanol (100 ml.),dl-l3-ethyl-3-(hydroxy)gona-1,3,5(10)-trien-17'one. Stir the mixture foran additional one-half hour and remove the methanol in vacuo. Suspendthe dry salt in DMSO 100 ml.). Add to the suspension a solution ofcyclobutylmethyl tosylate (2.5 g.) in DMSO ml.). Let stand at roomtemperature overnight, with stirring. Add water (300 ml.) with stirringand extract the mixture with ether. Remove the solvent from the dryextract in vacuo. Suspend the residue in benzene (50 ml.), triturate andfilter. Pass the filtrate through a column of Florex. Remove the solventfrom the filtrate in vacuo. Recrystallize the residue, a clear oil, frommethanol to get the product (925 mg.), mp. 100102C.; 2 5;; 5.78 p.

ANALYSIS Calcd. for C H O C, 81.77; H, 9.15.

Found: C, 81.30; H, 9.14.

EXAMPLE XV dl- 1 3-Ethyl-3-(cyclobutylmethyloxy)- l 8, l 9-dinor-17a-pregnal ,3 ,5( 10)-trien-20-yn-1 701 Suspenddl-l3-ethyl-3-(cyclobutylmethyloxy)gonal,3,5(l0l0)-trien-l7-one (1.0 g.)in dry DMSO ml.) in a flask equipped with a magnetic stirrer, a dryingtube and a gas inlet. Saturate the suspension with dry acetylene gas forone hour. Add lithium acetylideethylenediarnine complex in two aliquots(2.0 g.), one and one-half hour apart, continuing passing acetylene gasand stirring for a total of three and one-half hours after the firstaliquot has been added. Pour the brown black mixture into ice water andlet stand for one-half hour. Hxtruct the mixture with ether. Remove thes0lvent from the dry extract in vacuo. Suspend and trimrate the residuein benzene. Filter. Pass the filtrate through a column of Florex. Removethe solvent from 18 the filtrate in vacuo. Dissolve the residue indichloromethane, add charcoal and heat on a steambath. Filter through abed of Super Cel. Remove the solvent in vacuo. Dissolve the residue inether and filter through cotton. Remove ether on steam bath and pumpinto a dry glass (125 mg.) M 2.95, 3. 1p.

EXAMPLE XVI dl-l 3-Ethyl-3-( cyclobutylmethoxy )gona- 1,3,5(l0)-trien-17/3ol Dissolve dll 3-ethyl-3-(cyclobutylmethoxy)gona-1,3,5(10)-trien-17-one (1.5 g.) in methanol ml.). Add sodium borohydride(1.5 g. with stirring in small aliquots over a period of 1 hour. Stirthe mixture for three hours. Add water (100 1111.) slowly with stirring.Extract the mixture with ether. Remove the solvent from the dry extractin vacuo. Dissolve the residue in dichloromethane, add charcoal and heaton a steambath. Filter through a bed of Super Cel. Evaporate thefiltrate to a residue in vacuo. Recrystallize the residue from methanolto get the title product (500 mg), mp. 1l2-l 16 C.; X 3.08 t.

1. A compound selected from those having the formula:

wherein R is (lower)alkyl; R is selected from the group consisting ofcyclobutylmethylene and cyclopropylmethylene; R is selected from thegroup consisting of hydroxy and hydrogen; R is selected-from the groupconsisting of hydrogen, (lower)a1kyl, (lower)alkenyl, (lower)alkynyl andhalo(lower) alkynyl and R is hydroxy; R and R together are 0x0 or areconcatenated to form ethylenedioxy; the dotted lines represent optionalunsaturation; and the symbol (2) indicates aor B-configuration.

2. A compound as described in claim 1, which is:d-3-(cyclobutylmethyloxy)estral ,3,5( l0)-trien-l 7- one. 3. A compoundas described in claim 1, which is: d-3-(cyclobutylmethyloxy)- 1 9-norl7a-pregna- 1,3,5( l0)-trien-20-yn- 1 7-01. 4. A compound as described inclaim 1, which is: dl- 1 3-ethyl-3-(cyclobutylmethoxy)gonal ,3,5( 10)-trien-l7-one. 5. A compound as described in claim 1, which is: dl-l3-ethyl-3-(cyclobutylmethoxy)-l 8,19-dinor- 17a-pregna-1,3,5(l0)-trien-20-yn- 1 7-01. 6. A compound as described in claim I, whichis: d-S-(cyclopropylmethnxy)cstrnl ,3,5( l0 )-tricn-l 7- one. 7. Acompound as described in claim 1, which is:

e )alkylgona-(and 8-isogona)-1,3,5(l0)-tri 10 17-one of the formula:

and the A A A-, A and the A dehydro analogs thereof, wherein R is(lower)alkyl; R is selected from the group consisting of cyclobutyl,cyclobutylmethylene and cyclopropylmethylene; R is selected from thegroup consisting of hydroxy and hydrogen; the dotted lines representoptional unsaturation; and the symbol (5) indicates aor B-configuration, which comprises forming a 3-ether derivative of acolrlresponding 3-hydroxyl steroid compound of the form a:

wherein R and R, are as hereinabove defined by the steps of:

a. reacting said 3-hydroxyl steroid with at least about one equivalentof an alkali metal or alkaline earth metal (lower)-alkoxide in a(lower)alkanol medium until conversion of the 3-hydroxyl group to thecorresponding anionic form is substantially complete;

b. displacing said (lower)alkanol medium with an inert organic solventmedium;

c. reacting the mixture of Step (b) with at least about one equivalentof a compound of the formula X-Y, wherein X is selected from the groupconsisting of cyclobutyl, cyclobutylmethyl and cyclopropylmethyl and Yis a halide or tosylate group; and

d. recovering the product of Step (c). 11. A process as defined in claim10 wherein, in Step (a); said alkali metal (lower)alkoxide is sodiummethoxide and said (lower)alkanol medium' is I is carrie u a a tem e aur f from about 20C. to about or a pgriod o? fi'om about 2 hours toabout 48 hours.

14. A process as defined in claim 10 wherein, in Step (c), said halideis bromide.

15. A process as defined in claim 10 wherein d-3- (cyclobutyloxy)estra-l,3,5( l0)-trien- I 7-one IS prepared by the steps of: l

a. reacting d-estrone with sodium methoxide in methanol;

b. removing the methanol by vacuum distillation and addingdimethylsulfoxide;

c. reacting the mixture of Step (b) with cyclobutylbromide; and

d. recovering the product by removing the solvent by distillation in avacuum.

16, A process as defined in claim 10 wherein d-3-(cyclobutylmethyleneoxy)estra-l ,3 ,5( l 0 )-trienl 7-one is prepared bythe steps of:

a. reacting d-estrone with sodium methoxide in methanol;

b. removing the methanol by vacuum distillation and addingdimethylsulfoxide;

c. reacting the mixture of Step (b) with cyclobutyl' methyl tosylate;and

d. recovering the product by extracting the mixture of Step (0) withether and water and distillation in a vacuum.

17. A process as defined in claim 10 wherein dl-l3-ethyl-3-(cyclobutylmethyloxy)gonal ,3,5 l O)-trienl7-one is prepared bythe steps of:

a. reacting dl-l 3-ethyl-3-(hydroxy)-gona-l,3,5( l0)- trienl 7-one withsodium methoxide in methanol;

b. removing the methanol by vacuum distillation and addingdimethylsulfoxide;

creacting the mixture of Step (b) with cyclobutylmethyl tosylate; and

d. recovering the product by adding water to the mixture of Step (c),extracting with ether and distilling the extract in a vacuum.

18. A process as defined in claim 10 wherein d-3- (cyclopropylmethoxy)estra-l ,3 ,5( l0)-trienl 7-one is prepared by the steps of:

a. reacting d-estrone with sodium methoxide in methanol;

b. removing the methanol by vacuum distillation and addingdimethyl-sulfoxide;

c. reacting the mixture of Step (b) with cyclopropylmethyl tosylate; and

d. recovering the product by adding water to the mixture of Step (c),extracting with ether and distilling the extract in a vacuum.

2. A compound as described in claim 1, which is:d-3-(cyclobutylmethyloxy)estra-1,3,5(10)-trien-17-one.
 3. A compound asdescribed in claim 1, which is: d-3-(cyclobutylmethyloxy)-19-nor-17Alpha -pregna-1,3,5(10)-trien-20-yn-17-ol.
 4. A compound as described inclaim 1, which is:dl-13-ethyl-3-(cyclobutylmethoxy)gona-1,3,5(10)-trien-17-one.
 5. Acompound as described in claim 1, which is:dl-13-ethyl-3-(cyclobutylmethoxy)-18,19-dinor-17 Alpha-pregna-1,3,5(10)-trien-20-yn-17-ol.
 6. A compound as described in claim1, which is: d-3-(cyclopropylmethoxy)estra-1,3,5(10)-trien-17-one.
 7. Acompound as described in claim 1, which is:d-3-(cyclopropylmethoxy)-19-nor-17 Alpha-pregna-1,3,5(10)-trien-20-yn-17-ol.
 8. A compound as described in claim1, which is: dl-13-ethyl-3-(cyclobutylmethoxy)gona-1,3,5(10)-trien-17Beta -ol.
 9. A compound as described in claim 1, which is:d-3-(cyclobutylmethoxy)estra-1,3,5(10)-trien-17 Beta -ol.
 10. A processfor the preparation of a 3-substituted-13-(lower)alkylgona-(and8-isogona)-1,3,5(10)-trien-17-one of the formula:
 11. A process asdefined in claim 10 wherein, in Step (a), said alkali metal(lower)alkoxide is sodium methoxide and said (lower)alkanol medium ismethanol.
 12. A process as defined in claim 10 wherein, in Step (b),said inert organic solvent medium is dimethyLsulfoxide.
 13. A process asdefined in claim 10 wherein Step (c) is carried out at a temperature offrom about 20*C. to about 100* C. for a period of from about 2 hours toabout 48 hours.
 14. A process as defined in claim 10 wherein, in Step(c), said halide is bromide.
 15. A process as defined in claim 10wherein d-3-(cyclobutyloxy)estra-1,3,5(10)-trien-17-one is prepared bythe steps of: a. reacting d-estrone with sodium methoxide in methanol;b. removing the methanol by vacuum distillation and addingdimethylsulfoxide; c. reacting the mixture of Step (b) withcyclobutylbromide; and d. recovering the product by removing the solventby distillation in a vacuum.
 16. A process as defined in claim 10wherein d-3-(cyclobutylmethyleneoxy)estra-1,3,5(10)-trien-17-one isprepared by the steps of: a. reacting d-estrone with sodium methoxide inmethanol; b. removing the methanol by vacuum distillation and addingdimethylsulfoxide; c. reacting the mixture of Step (b) withcyclobutylmethyl tosylate; and d. recovering the product by extractingthe mixture of Step (c) with ether and water and distillation in avacuum.
 17. A process as defined in claim 10 whereindl-13-ethyl-3-(cyclobutylmethyloxy)gona-1,3,5(10)-trien-17-one isprepared by the steps of: a. reactingdl-13-ethyl-3-(hydroxy)-gona-1,3,5(10)-trien-17-one with sodiummethoxide in methanol; b. removing the methanol by vacuum distillationand adding dimethylsulfoxide; c. reacting the mixture of Step (b) withcyclobutylmethyl tosylate; and d. recovering the product by adding waterto the mixture of Step (c), extracting with ether and distilling theextract in a vacuum.
 18. A process as defined in claim 10 whereind-3-(cyclopropylmethoxy)estra-1,3,5(10)-trien-17-one is prepared by thesteps of: a. reacting d-estrone with sodium methoxide in methanol; b.removing the methanol by vacuum distillation and addingdimethyl-sulfoxide; c. reacting the mixture of Step (b) withcyclopropylmethyl tosylate; and d. recovering the product by addingwater to the mixture of Step (c), extracting with ether and distillingthe extract in a vacuum.